1. Field of the Invention
The present invention relates in general to implants for prevention and treatment of vascular restrictions. More specifically, the present invention relates to stents made of metal or alloy to which is admixed at least one naturally occurring or enriched stable radioactivatable isotope that when activated safely and uniformly emits desired dosages of radiation for prevention and treatment of various types of vascular restrictions when implanted in blood vessels.
2. Description of the Prior Art
According to the American Heart Association, in 1995, almost one million Americans lost their lives because of heart disease, more than any other single illness, and approximately seventeen million persons are at risk of a first heart attack. An estimated one hundred million people in the United States, Japan and the five leading countries of the European Union have clinical or subclinical atherosclerosis. New estimates suggest that carotid artery disease, another vascular disorder, is responsible for half of the 700,000 strokes that occur in the United States annually. Each year, more than 150,000 people die from stroke. Peripheral artery disease restricts blood flow to the leg, the kidney (frequently requiring dialysis), and to other organs. These devastating ailments are the leading cause of disability and the cost to the United States health care system was $274.2 billion last year, a figure that is expected to increase dramatically as the baby boom generation ages.
A common treatment for vascular restrictions is angioplasty, also known as percutaneous transluminal angioplasty, which involves threading a flexible shaft into an artery and briefly inflating a balloon catheter that stretches the blood vessel open and squeezes away the obstruction. It is a non-surgical procedure and therefore is much less expensive and much safer than the typical alternative-bypass surgery. In 1995, the average cost of this procedure was $20,370. Approximately 6.9 million diagnostic and interventional catheterizations of this type are performed annually.
Although angioplasty is used to restore blood flow, the technique is only a partial solution to find a cure for vascular disease and in particular, to treat restenosis, a fairly common complication following angioplasty. Restenosis is a reclosing of arteries as a result of injury to the arterial wall during the angioplasty procedure, and can necessitate repeat angioplasty procedures or bypass surgery, with substantially higher cost and risk to the patient. The condition affects up to forty percent of patients undergoing an angioplasty procedure, usually within six months. Long term restenosis may cause symptoms such as chest pain and fatigue, and an increased danger of heart attack, stroke or kidney failure. Patients also continue to be at risk of thrombogenesis (blood clotting), and atherosclerosis (hardening of the arteries). It can lead to recoil which is the mechanical collapse of dilated vessel segment in response to vascular injury. Plaque is also generated within blood vessels after angioplasty, which restricts blood flow.
Restenosis is believed to be caused by smooth muscle cell proliferation or neointimal proliferation in the vessel wall, a repair response of the body prompted by the arterial trauma resulting from angioplasty. This hyperplasia of smooth muscle cells narrows the lumen opened by angioplasty. Restenosis is also believed to be caused by elastic recoil, which is contraction of the vessel wall to its previous position after having been stretched by balloon angioplasty, and by vessel wall remodeling, which is the formation of scar tissue where balloon angioplasty caused trauma. Thus, methods for treating restenosis have focused on inhibiting such remodeling and hyperplasia of smooth muscle cells and on implants to prevent recoil closure of arteries.
Methods for inhibiting hyperplasia of smooth muscle cells have employed intravascular radiotherapy ("IRT"). Radiation is commonly used to treat catastrophic diseases such as cancer because of its effectiveness in reducing the hyperproliferation of cancerous cells. Localized radiation inhibits cellular proliferation, including smooth muscle proliferation, and has been shown to inhibit the typical wound healing process. It is believed that radiation breaks down genetic material in the vascular endothelium causing cell death, known as apoptosis, thus preventing cellular division. There is a dose dependent hyperplastic response and a marked reduction in smooth muscle cell build-up. Which component of the arterial wall serves as the target tissue for radiation still needs to be determined. What has been determined is that intraarterial radiation effectively shuts down the neointimal proliferative response process.
In early intravascular clinical trials for the prevention and treatment of restenosis, high-dose rate ionizing radiation delivery systems containing wire or seeds of radioisotopes such as iridium-192, a highly penetrating gamma ray emitter, and long-lived strontium-90 have demonstrated efficacy. However, iridium-192, and the devices utilized for endovascular afterloading-irradiation treatment with iridium-192, have shortcomings. As noted above, iridium-192 is principally a gamma ray emitter, and given the high dose utilized, the gamma ray emissions can travel a considerable distance in the surgical suite, and thus can irradiate the patient's healthy tissue and cells en route to the target site at the distal end of an afterloading probe. Iridium-192 based therapies can have exposure times ranging from 200 seconds to twenty minutes. Should the distal end of the delivery catheter containing the iridium-192 wire or seed be blocked or delayed in the tortuous journey to the target site, endothelial membrane could be overexposed to the radiation source, resulting in weakening of healthy tissue as well as the stenosed artery wall, resulting in cellular damage. Physicians and technicians may also receive an excessive radiation dose during a procedure involving the use of iridium-192. Also, there are disposal problems given the 73.83 day half-life of iridium-192.
Furthermore, the vascular surgeon cannot adjust the actual dose other than by extending dwell time in the artery. Dosimetry must be carefully calculated taking into account decay time and other factors. The approach of using a short-term, high-dose application can present other potentially acute problems, including maintenance of sterility. Given the high doses of iridium-192 utilized, even with lead shielding, the radioactive emissions travel a considerable distance in a surgical suite.
Similarly, strontium-90 has a 29.1 year long half-life, which also presents a number of other problems. This radioisotope is a beta emitter and only travels a short distance. However, strontium-90 also has inherent risks of patient contamination and device sterility problems arising from multiple patient use. Radioactive waste disposal difficulties arise because of its long half-life and unrestricted disposal requires 10 half lives, or 291 years. Similarly, should the distal end of the delivery catheter containing the strontium-90 source be stuck in the tortuous route to the target site, healthy tissue and cells will be irradiated. Overexposure to radiation from the high-dose strontium-90 applicator irradiation may weaken healthy or stenosed artery walls. The application of short-term high-dose irradiation requires the presence of a radiation therapist or oncologist as well as a cardiovascular surgeon or interventional radiologist, resulting in increased procedural cost and time.
Attempts have been made to deliver radiation doses by coating an implant with other pure beta emitting radioisotopes such as phosphorus-32 and yttrium-90. A fundamental problem with pure beta emitting radioactive coatings such as phosphorus-32 or activated wire made from monoisotopic yttrium is that the radioactivity cannot be precisely calibrated in the microcurie range in a typical catheterization laboratory setting using a conventional well counter as a dose calibrator. Furthermore, those skilled in the art will recognize that uniform in-situ implantation, such as sputter coating, plating or ion deposition of phosphorus-32 (which has a 14.29 day half-life) onto a stainless steel surface is complex and problematic. Ion deposition or implantation of the stable isotope is a line-of-sight process, and as a result, the radioactive coating and the isodose/radiation field it produces may not be uniform on the outer circumference. Thus, it is possible that only one side of the metal surface of the delivery system will emit radiation and the radiation dose emitted and delivered to tissue may vary considerably.
In another approach to produce a radioisotope delivery system for the treatment of restenosis, a radioactive liquid-filled balloon containing rhenium-186 is utilized. Those skilled in the art would recognize that the balloon could rupture spilling its contents within the blood stream or spraying clinicians and technicians. Also, there are logistical problems filling, handling and disposing of radioactive solutions in a catheterization laboratory or department of nuclear medicine.
Thus, while it has been shown that mild exposure to low level radiation intravascular radiotherapy is an effective treatment for coronary and peripheral artery disease and restenosis or target vessel revascularization in particular, and for the management of certain constrictive cancers, current technologies do not adequately address problems associated with the effects of long-term implantation of radioactive materials or short-term high-dose therapy. Uncertainties continue to remain associated with radiation safety issues, uniform radiation delivery, dose calibration, a number of procedural shortcomings in performance and design characteristics, including delivery system flexibility and radial strength, reactivity, associated hemorrhagic complications, risk of contamination and sterility, long term patency and radioactive waste disposal problems, which the present invention aims to remedy.
Among the implant treatments are metal stents which have been developed and used to prevent and treat restenosis. A stent is a implantable small tubular structure consisting of a slotted cylinder, wire mesh, or helical coil spring that acts as a support after deployment within a coronary or peripheral artery. Stents prevent the inner walls of a blood vessel from spontaneous blockage and reclosure. Coronary stenting has made a significant difference in preventing restenosis. Stents provide an effective form of treatment by reducing the incidence rate of restenosis from one in two patients to about one in three. When stents are used in conjunction with conventional angioplasty, those treated are less likely to relapse.
In 1996 more than 400,000 stent implantation procedures were performed. Stent usage has risen tenfold in only three years. In 1997, approximately thirty percent of patients undergoing balloon angioplasty received one or more stents. By 2001, it is projected that worldwide, as many as two out of every three angioplasty procedures will involve the use of stents. It is anticipated that the number of stent placements will continue to increase. Recent industry reports suggest that by the year 2001, there will be 800,000 coronary stenting procedures performed worldwide and more than 100,000 will utilize radiation to prevent clinical arterial restenosis.
Stents are commonly made of metal or alloys, and advances in stent technology have included the use of nickel-titanium alloys, so called "Nitinol" family alloys, as stent material. Nitinol alloys possess temperature sensitive shape-memory properties, and these properties have been used to create more easily implantable stents which can be deformed for implantation and then reconfigured into the desired size and shape within the blood vessel to be reinforced, such reconfiguration being triggered by changing the stent's temperature once it is implanted within the blood vessel. The Nitinol material is typically formed into a helical wire coil or tubular structure with the diameter of the helical coil being equal to or slightly greater than that of the blood vessel in which it is intended to be used as a stent. After the helical coil is made it is heated to fix the shape of the coil in the memory of the Nitinol. The wire of the helical coil is then wound to form a helical coil having an appreciably smaller diameter than that of the first helical coil, and smaller than the diameter of the blood vessel in which it is to be inserted. This smaller diameter coil is then placed in the intended blood vessel at the place where the angioplasty balloon was previously inflated. After placement in the blood vessel, the coil is heated either by the internal blood vessel temperature or by passing warm saline solution through the catheter used to deploy the stent. Upon being heated the nitinol returns to its first larger diameter and presses firmly against the interior walls of the blood vessel, where it is left as a support to prevent restenosis. There are still problems, however, in that tissue may proliferate within the stent and in the areas of the blood vessel other than where the stent is implanted.
More recent advances in this field have included the combination of the above two treatments, i.e., radiation therapy and stent implantation, through the development of radioactive stents. Stents have been developed utilizing activated radioisotopes that are either placed inside the stent, alloyed into the metal from which the stent is made, or coated onto the exterior surface of the stent. However, as previously noted, short-term high-dose radiation treatment can result in a weakening the walls of the artery and cause cellular damage, the patient may also be at greater risk of aneurysm and thrombus. High dose delivery systems are not intended to remain implanted and are used again and again in patients, posing sterilization risks.
The problems and drawbacks of intraarterial irradiation as it is currently practiced are manifold. This form of radiation treatment currently involves the use of external beam gamma emitting radiation therapy, or short-term ultra high-dose radiation delivery systems such as afterloaders, permanently implantable radioactive metallic stents, and pure beta emitting or gamma emitting stents. As previously noted, in high-dose short-term radiotherapy the use of long-lived isotopes is the norm and delays often occur during implantation of the radiation source because of the tortuous passage to reach the targeted vessel and collateral damage may occur on the way to or at the stenosed site. The stents in current use do not yet adequately address problems associated with the effects of very high doses of localized therapy or the long-term results of permanent implantation of radioactive stents.
Additionally, conventional stent radiation dose loading techniques such as plating or sputtering may not always achieve a tenacious adhesion of the phosphorus-31 stable isotope. Furthermore, deposited surface coatings on a stainless steel or tantalum stent consisting of phosphorus-32 or other radioisotope as particulate matter can shed, shear off, leach, or come loose at any time releasing radiation and particulate in undesirable locations such as vital organs. Radioactive metal stents are not readily coated with antirestenotic or antineoplastic agents for adjuvant or combination therapy nor are they bioerodable or biodegradable. Another shortcoming of phosphorus-32 stents is that disposal of unused stents requires storage-in-decay of 143 days.
Low energy x-ray emitters such as iodine-125 and palladium-103 have been employed as an alternative to reduce the risks of cellular damage associated with more powerful gamma ray emitters such as iridium-192 and cobalt-60, but may not have suitable isodose ranges for treating large diameter vessels, and therefore are of less utility.
Other stents have been produced of wire which is itself radioactivatable. Radioactive stents made of irradiated yttrium wire present other problems including giving rise to undesirable, long-lived strontium-90 (29.1 yr. half-life) during activation as well as a short 2.67 day yttrium-90 half life. Also, yttrium is not ductile nor does it have flexibility, compressibility or shape memory characteristics, properties that are desired in stent applications for ease of implantation and deployment.
Still another problem that affects uniform radiation dose delivery in radioactive stent applications is accurate radiation source centering, particularly when using high dose gamma ray emitters such as iridium-192. Accurate source centering is difficult to achieve precisely and consistently. If the radiation source is not centered, a higher than desired level of radiation may be delivered to one side or the other of the occluded passageway, resulting in tissue damage on the overly irradiated side and insufficient dosage to the under irradiated side.
Thus, even with current stenting technology there is a need to address the shortcomings of current methods of management, to improve upon the clinical efficacy of conventional stenting, characterized by a difficulty in implantation because of kinking, and current stents can result in stiffness, migration, wall-thinning aneurysm formation, limited flexibility, medial atrophy and intrastent restenosis, among other problems. Specifically, despite recent advances in radioactive stent technology, there are still needs for improvements in the following areas, among others: radiation safety issues, uniform radiation delivery, imprecise localized dose delivery, deep penetration and irradiation of healthy tissue by high dose application, dose calibration, procedural shortcomings in performance and design characteristics, including radioactive coating deterioration, flaking, stent flexibility and radial strength, reactivity, risks associated with hemorrhagic complications, risk of contamination patient-to-patient when using the same radiation applicator, sterility, long term patency and radioactive waste disposal problems, and the potential for exposure to radiation by physicians and technicians.
Furthermore, resolution of the above-described shortcomings may allow for stents to be useful for prevention and treatment of other conditions than just restenosis. In the United States, Japan and the European Union, about one million new cases of constrictive cancers are diagnosed annually. Conventional stents are being utilized to maintain airways open in tracheobronchial stenoses, nasolacrimal and large airway system blockages. Because radioactive stenting is similar in some respects to high dose brachytherapy, the procedure may also be useful to inhibit the spread of cancer in the esophagus, gall bladder, biliary, renal and transhepatic system, for treatment of prostatic carcinoma, and benign prostatic hyperplasia. Enhanced patient outcomes may become a reality by using a radioactive stent to stop recurrent tumors from proliferating while keeping passageways free of obstructions. Applications for improved stents overcoming the above-described shortcomings include treatment of not only carotid, but also iliac and other peripheral artery disease.